Ca2+ flux in myocardial cells is an important factor for myocardial contraction. In recent years, many reports have shown that abnormal Ca2+ regulation (abnormal calcium handling) in myocardial cells is closely related to onset of heart failure (see Non-Patent Documents 1 and 2). In general, Ca2+ flux in a myocardial cell is as follows. A myocardial cell contains sarcoplasmic reticulum serving as a Ca2+ pool, and influx of extracellular Ca2+ triggers Ca2+ release from the sarcoplasmic reticulum via ryanodine receptor (RyR) into the cytoplasm. This increases cytoplasmic Ca2+ concentration, resulting in myocardial contraction. Meanwhile, myocardial dilation requires a decrease in cytoplasmic Ca2+ concentration, which is attained through Ca2+ reuptake into the sarcoplasmic reticulum by means of sarco(endo)plasmic reticulum Ca-ATPase (SERCA). Excess Ca2+ which has been initially taken up from the outside of the cell is discharged to the outside thereof by means of Na+—Ca2+ exchange pump (NCX). Recent studies have focused on the sarcoplasmic reticulum, which serves as a Ca2+ pool in a myocardial cell, in view that the sarcoplasmic reticulum is related to abnormal calcium handling, and depletion of Ca2+ in the sarcoplasmic reticulum has been shown in the case of heart failure. Therefore, it may be possible to develop an anti-heart failure drug or an antiarrhythmic drug on the basis of a new concept of targeting an increase in Ca2+ concentration in the sarcoplasmic reticulum to a normal level.
Conventionally, studies on a mechanism of abnormal calcium handling have focused on lowering SERCA activity. In practice, overexpression of SERCA has shown to improve cardiac contraction performance and cardiac relaxation performance (see Non-Patent Document 3). However, heart failure patients do not necessarily exhibit a change in SERCA amount or SERCA activity (see Non-Patent Document 4). Therefore, in recent years, studies have focused on involvement of RyR, in addition to SERCA, in the abnormal calcium handling mechanism.
RyR is a protein which binds specifically to ryanodine, which is an ergot alkaloid. RyR has a tetrameric structure containing subunits of about 5,000 amino acids, and is considered to form a foot structure on the N-terminal side and a channel on the C-terminal side. RyR is classified into three subtypes; i.e., RyR1, which is localized in skeletal muscle and the brain (in particular, the cerebellum); RyR2, which is localized in myocardium, smooth muscle, and the brain (entire brain); and RyR3, which is present in the brain (in particular, the hippocampus and thalamus), smooth muscle, and skeletal muscle. In the present invention, the ryanodine receptor encompasses all these subtypes, but is preferably RyR2. As described above, RyR2 is a homotetramer containing four subunits of about 5,000 amino acids, in which one subunit is bound to one molecule of FK506-binding protein 12.6 (FKBP12.6). Conceivably, when RyR2 is bound to FKBP12.6, the structure of RyR2 is stabilized, whereas when FKBP12.6 is dissociated from RyR2, Ca2+ is released from the sarcoplasmic reticulum to the cytoplasm.
As has been known, FKBP12.6 is dissociated from RyR2 through phosphorylation with protein kinase A (PKA). In heart failure patients, hyperphosphorylation with PKA causes dissociation of FKBP12.6 (60% or more), which results in enhancement of Ca2+ sensitivity of RyR2, leading to abnormal leakage of Ca2+ from the sarcoplasmic reticulum (see Non-Patent Document 5).
RyR2 mutation has been observed in several heart-related diseases [CPVT (catecholaminergic polymorphic ventricular tachycardia), FPVT (familial polymorphic ventricular tachycardia), and ARVD (arrhythmogenic right ventricular dysplasia)] (see Non-Patent Document 6). In practice, in vitro studies have shown that CPVT-related RyR2 mutation reduces the affinity of RyR2 to FKBP12.6, and enhances the sensitivity of RyR2 to phosphorylation (see Non-Patent Document 7).
In addition, experiments employing the sarcoplasmic reticulum of the left ventricular myocardium of a dog model with heart failure induced by high-frequency right ventricular pacing have shown that abnormal Ca2+ leakage via RyR2, which is observed in the heart failure model, is attributed to a change in RyR2 structure associated with reduction of the stoichiometric composition of FKBP12.6 (see Non-Patent Document 8).
Recent studies have shown that JTV519, which is a 1,4-benzothiazepine derivative, corrects abnormal Ca2+ leakage via RyR2 (see Non-Patent Document 9). JTV519 was developed as a therapeutic drug for ischemic disorders, and was subjected to clinical tests. According to Yano, M., et al., RyR2 is an effective target of JTV519, and a drug may be developed on the basis of a new concept of correcting calcium handling through the RyR2-stabilizing effect of JTV519.
In view of the foregoing, in the art, demand has arisen for development of a substance exhibiting the effect similar to that of JTV519 (i.e., RyR2-stabilizing effect), and exhibiting no side effects.    Non-Patent Document 1: Beuckelmann, et al., Circulation, 85, 1046-1055 (1992)    Non-Patent Document 2: Gwathmey, et al., Circ Res, 61, 70-76 (1987)    Non-Patent Document 3: Baker, et al., Circ Res, 83, 1205-1214 (1998)    Non-Patent Document 4: Munch, et al., J Mol Med, 76, 434-441 (1998)    Non-Patent Document 5: Marx, et al., Cell, 101, 365-376 (2000)    Non-Patent Document 6: Marks, Circulation, 106, 8-10 (2002)    Non-Patent Document 7: Wehrens, et al., Cell, 113, 829-840 (2003)    Non-Patent Document 8: Yano, et al., Circulation, 102, 2131-2136 (2000)    Non-Patent Document 9: Yano, et al., Circulation, 107, 477-484 (2003)